The goal of this Clinical Investigator Development Award is to further development and training of an independent academic investigator in anesthesiology and physiology. The research will emphasize a new technology that permits three-dimensional reconstruction of the pulmonary airways and vessels in vivo. It has two primary objectives, the first to establish the local responsiveness of conducting airways to various stimuli, the second to determine the extent of interaction between the pulmonary vasculature and conducting airways. Specific research aims will first be directed toward the testing of the response of airways to a variety of interventions relevant to standard airways function tests used to assess lung disease. We will test the mechanism and extent of regional airway response heterogeneity in different size airways in vivo to bronchoconstrictors and bronchodilators that have been reported to differentially constrict portions the airway tree or work through different pharmacologic pathways. I will also be able to evaluate the effect of the pulmonary vasculature on the airway tree. Preliminary data have shown that even relatively large conducting airways can be partially obstructed when the pulmonary vasculature pressure is increased. We hypothesize that this interaction between the vasculature and airway tree will affect the responses of the airways to endogenous and exogenous stimulation. To test this hypothesis we will quantify airway and regional vascular distensibility and their interaction using computerized reconstruction of the in vivo airway and vascular trees. We will also determine the progressive effects of increasing pulmonary edema on in situ airway size and regional vascular dimensions. The airway and vascular morphometric data will be applied to existing analytical models of the airway and vascular tree. I will also test the extent of regional airway response heterogeneity through the airway tree to physiologic stimuli known to worsen pulmonary status in clinical conditions, specifically, hypervolemia, hypovolemia, hypercapnia, and hypoxia. The results from all of these investigations will have a significant impact on our understanding and interpretation of pulmonary function in the clinical setting.